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D. C. Dean, Y. Liu; Taz-Tead1 Links Cell-Cell Contact to Zeb1 Expression, Proliferation and Dedifferentiation in Retinal Pigment Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4096.
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© ARVO (1962-2015); The Authors (2016-present)
The Hippo signaling pathway imposes the cell contact inhibition which establishes organ size and tissue topology from Drosophila to mammals. This pathway regulates activity of the Yap and Taz transcription factors, which link epithelial-mesenchymal transition (EMT) to cell proliferation. Here, we provide evidence that Taz and its co-activator Tead1 regulate expression of the EMT transcription factor Zeb1 to control RPE cell proliferation and differentiation.
Real time PCR was used to examine mRNA expression during RPE dedifferentiation in primary cultures of RPE cells and following knockdown of Yap and Taz by lentivirus shRNA. Immunofluorescence was used to follow subcellular localization of proteins in cells. Chromatin immunoprecipitation was used to detect Taz at the Zeb1 promoter in vivo.
Zeb1 is overexpressed during RPE dedifferentiation leading to cell proliferation, EMT and repression of the RPE specification transcription factor gene Mitf. Taz-TEAD1 translocation to the nucleus coincides with loss of cell-cell contact and with onset of Zeb1 expression in the nucleus. shRNA knockdown of Taz prevented overexpression of Zeb1 and in turn it prevented proliferation, repression of Mitf and Mitf target genes and EMT when RPE cells were placed in primary culture. Taz binds to the Zeb1 promoter in vivo, suggesting that it directly induces Zeb1 transcription.
These results provide evidence of a molecular mechanism linking cell-cell contact to cell proliferation and dedifferentiation in RPE cells.
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